Incidence Trends of Vulvar Cancer in the United States: A 20‐Year Population‐Based Study

ABSTRACT Background Despite being uncommon, vulvar cancer is a serious health concern with a 5‐year relative survival rate of 71%. Aims The objective was to investigate the incidence rates of this disease across different racial, ethnic, and histological subgroups in the United States, as well as the effects of the COVID‐19 pandemic on this cancer. Methods We used the Surveillance, Epidemiology, and End Results (SEER) 22 database. The International Classification of Diseases for Oncology Version 3 topologic code C51 was assigned for vulvar cancer. Average annual percent change (AAPC) and the pairwise comparison with the parallelism and coincidence were reported. Counts and age‐adjusted incidence rates per 100 000 individuals with their corresponding 95% confidence intervals (CIs) were reported. Results The age‐adjusted incidence rate of vulvar cancer was 2.40 (95% CI, 2.38–2.43) over the period 2000–2019, with an AAPC of 0.80 (95% CI, 0.63–0.99). By race/ethnicity, only non‐Hispanic Whites had an increasing trend over 2000–2019 (AAPC: 1.30; 95% CI, 1.07–1.54). The highest age‐adjusted incidence rate of vulvar cancer in the United States was for squamous cell carcinoma (SCC). There was a significant decrease in the age‐standardized incidence rate of vulvar cancer in all races/ethnicities in all age groups (AAPC: −10.15; 95% CI, −15.35 to −4.94) over 2019–2020. Also, the incidence rates and incident numbers of vulvar cancer increased with aging and peaked at the 85+ age group. Conclusion There was an increase in the incidence rate of vulvar cancer in all races, with a significantly increased trend in non‐Hispanic White women from 2000 to 2019. SCC displayed the highest incidence rate among vulvar cancer histological types. It is recommended to conduct further research to identify the relevant risk factors of vulvar cancer in the United States.

cancer cases comprise squamous cell carcinoma (SCC), the most prevalent histologic type [5].A study of the Dutch Cancer Registry conducted between 1989 and 2010 showed that the typical distribution of histologies was the highest for SCC (81%) and basal cell carcinoma (BCC) (8%) [5].However, other studies have found other histologies more prevalent than BCC such as malignant melanoma or invasive Paget's disease [6].
Over the last two decades, the incidence of vulvar cancer has risen in the United States and other high-income regions.One study in the United States reported a consistent 1.2% annual rise in human papillomavirus (HPV)-associated vulvar cancer cases [2].Another study spanning from 2001 to 2018 noted an increase in overall vulvar cancer rates from 1.83 to 1.96 per 100 000 individuals [7].
Extensive epidemiological data indicate that race or ethnicity correlates with variations in cancer occurrence and fatality rates [8].The latest research indicates that the highest overall cancer incidence is observed in White individuals, closely followed by American Indian/Alaska Native and Black individuals.A study of 75 767 participants in the United States showed that Whites exhibited the highest average annual percentage increase, followed by Blacks, Asian/Pacific Islanders, and Hispanics for vulvar cancer [9].This study also evaluated vulvar cancer incidence based on its common histology types, reporting a rate of 77.7%, 6.94%, 5.31%, 1.15%, and 8.87% regarding SCC, adenocarcinoma, melanoma, sarcoma, and other histologies, respectively [9].Recognizing cancer incidence trends is instrumental in informing public health policies, clinical practices, and research initiative.Given its low incidence and various histological types, the data on vulvar cancer are scarce.With the constantly changing incidence rates of vulvar and other types of cancers, there is a need for extensive and more recent knowledge of this cancer's epidemiological trends.These data will be particularly useful in designing and implementing targeted prevention and intervention programs for susceptible populations.Previously, the vulvar cancer incidence was reported using the preceding iterations of the Surveillance, Epidemiology, and End Results (SEER) database in different time periods, including 1998-2003 [10], 1973-2010 [11], 2001-2017 [9], and 2001-2018 [7].Furthermore, prior research has not placed primary emphasis on vulvar cancer as their central subject [12,13], and those studies that have done so, have generally focused on previous version of the SEER database, did not report methodological elements such as the parallelism and coincident tests, and did not evaluate the incidence rates after the COVID-19 pandemic [7,9,14].Therefore, this paper aimed to identify patterns and trends in the incidence rates of vulvar cancer across demographically and morphologically variant subgroups in the United States in a 20-year time period by using the SEER database.Moreover, the effects of the COVID-19 pandemic on the incidence trends of vulvar cancer were investigated.

| Study Design and Data Source
It is a retrospective, population-based observational study.The SEER Program of the National Cancer Institute (NCI) is the only comprehensive population-based information source in the United States that provides information on patient survival rates as well as cancer stage at the time of diagnosis.The SEER 22 covers almost 48% of the US population [15].The SEER program routinely gathers information on the patient's demographics, primary tumor site, tumor morphology, stage at diagnosis, initial course of therapy, and vital status follow-up [15].The current study, used the SEER 22 database to estimate the incidence rates and annual percent changes (APCs) of microscopically diagnosed vulvar cancer from 2000 to 2020 [16].The SEER 22 database was accessed under the SEER Research Data Agreement for the 1975-2020 Data (November 2022 Submission) [17].

| Definitions
Cancer cases are reported as frequencies and percentages, and the incidence rate is expressed as cases per 100 000 population.The APCs of vulvar cancer for a dedicated period show the variation of rates at a constant proportion of the preceding year's rate.The average annual percent changes (AAPCs) describe the average of multiple APCs over the period.The race and ethnicity were classified as non-Hispanic White, non-Hispanic Black, and Hispanic, which includes White Hispanic and Black Hispanic patients.Because of the low sample size, the race and ethnicity groups of American Indian/Alaskan Native, Native Hawaiian, and Asian/Pacific Islander cases were only used to calculate the parameters of all races and ethnicities.Patients with vulvar cancer were identified based on the International Classification of Diseases for Oncology Version 3 code C51.The morphologies of vulvar cancer were classified as SCC (codes 8050-8089), BCC (codes 8090-8110), adenocarcinoma (codes 8140-8389), and other morphologies (codes other than 8140-8389, 8050-8089, and 8090-8110).

| Statistical Analysis
The SEER 22 database for 2000-2020 [2] was obtained from SEER*Stat, Version 8.4.1.2[18].The case selection was set to include only females with microscopically diagnosed vulvar cancer and known age; then, the included cases were stratified based on race, ethnicity, and morphology.The SEER*Stat Version 8.4.1.2[18] was used to estimate the age-standardized incidence rates based on the 2000 United States standard population and the associated 95% confidence intervals (CIs) with the Tiwari method [19].The Joinpoint Regression Program, Version 5.0.2 [20], was used to estimate the APCs, AAPCs, Joinpoint Regression modeling, parallelism test, and coincident test for age-standardized incidence rates [21].The year 2020 was the first year of the COVID-19 pandemic, leading to decreases in cancer screening and diagnosis, resulting in a fall in the majority of cancer sites' 2020 incidence rates [22].As a result, the 2020 incidence data may introduce bias into cancer incidence estimates; hence, it was omitted from Joinpoint trends and only displayed in illustrations.The APCs of vulvar cancer age-standardized incidence rates were estimated by generating the best fit of least-squares regression lines on the natural logarithm of the age-standardized incidence rate, setting the year of diagnosis as a regressor variable.The minimal number of observations between two Joinpoints and from the Joinpoint to either end of the data was set to two.For model selection, the permutation test with a total significance level of 0.05 and 4 499 permutations was used [21].The 95% CIs of APCs and AAPCs were calculated using a parametric method to determine whether the APCs and AAPCs were statistically different from zero.The pairwise comparison with the parallelism test was performed to examine whether the trends of the two groups over time were similar [23].Also, the pairwise comparison with the coincidence test was conducted to investigate whether the rates of the two groups over time were identical.
Non-Hispanic Whites had the highest incidence rate and the most significant upward trend, whereas non-Hispanic Blacks had a lower initial rate and a moderate nonsignificant increase in incidence.Hispanics, on the other hand, showed a nonsignificant decreasing trend in vulvar cancer incidence rates over the studied period.

| Effects of COVID-19 on Incidence Rates of Vulvar Cancer
There was a significant decrease in the age-standardized incidence rate of vulvar cancer in all races/ethnicities in all age groups (AAPC: −10.3).

| Age Patterns of Vulvar Cancer
The incidence rates and incident numbers of vulvar cancer increased with aging and peaked in the 85+ age group (Figure 2).Moreover, the incidence rates of adenocarcinoma increased ( with advancing age.Also, the incident cases of adenocarcinoma peaked in the 60-64 age group (Figure S9).There were also similar trends for incidence rates and incident cases of SCC (Figure S10), BCC (Figure S11), and other types of vulvar cancer (Figure S12).

| Discussion
The primary findings of the current study based on the data from the SEER Program over the years 2000-2019 demonstrated that the incidence rates of vulvar cancer were increasing in the United States.Non-Hispanic White women had the highest incidence rate for vulvar cancer, with a relatively increasing trend compared to others.Moreover, SCC had the highest incidence rate among vulvar cancer histotypes, with the highest incidence rate and relatively increasing trend in non-Hispanic Whites compared to other groups.
Our study revealed an increasing incidence rate of vulvar cancer in the United States from 2000 to 2019.In line with our results, a study by Zhou et al. based on the data obtained from the US Cancer Statistics (USCS) database over 2001-2018, indicated an increasing vulvar cancer incidence rate.The same study investigation similarly observed a notable decline in non-SCC vulvar cancer.However, our study did not identify any statistically significant alterations in histological types apart from SCC.This discrepancy may stem from the differing categorizations.In our study, non-SCC encompasses adenocarcinoma and BCC, whereas in the other study, non-SCC includes adenocarcinoma and several distinct histopathologies grouped under "other malignancies" [7].Furthermore, similar trends regarding overall vulvar cancer incidence rates were discovered in high-income countries.Another study comprising data from the Saarland Cancer Registry between 1974 and 2013 revealed a significant increase in the vulvar cancer incidence rate in Germany [24].Likewise, the results of a study retrieved from the United Kingdom Cancer Information Service from 1990-1992 to 2007-2009 showed a similar pattern [25].According to a previous study in the United States, HPV DNA was detected in almost 69% of patients with vulvar cancer, suggesting a potential link between HPV infection and the incidence of vulvar cancer [26].However, other global studies normally reported around 30%-40% of vulvar cancers as HPV positive [27].We theorize that the rising rates of vulvar cancer may be linked to increased HPV exposure, possibly influenced by changes in sexual behavior among women born after 1940, although other factors may also contribute [28,29].Moreover, results of a systematic review of 14 studies involving more than 14 000 women showed that vulvar lichen sclerosus elevates the likelihood of vulvar cancer, particularly when combined with differentiated vulvar intraepithelial neoplasia and as age progresses [30].In this regard, another large-scale cohort study in the United States highlighted that lichen sclerosis is underrecognition, particularly in younger, fertile women, although obstetrics/gynecologists diagnose and manage about half of these cases [31].Metabolic factors like diabetes mellitus or high body mass index, as well as immunocompromised states, are also other risk factors for the development of vulvar cancer [32].The increasing trend of diabetes mellitus globally and in the United States can also  explain the increase in incidence rates of vulvar cancer and suggests that maintaining metabolic health can be an option to help prevent vulvar cancer development [33].
HPV vaccination can effectively reduce the incidence of gynecological cancers, particularly cervical and vaginal cancers, with less impact on vulvar cancer due to its lower association with HPV [34].In this regard, a recently published article by Berenson et al. has found evidence that HPV vaccinations likely contributed to a decrease in the incidences of vulvar carcinoma in situ and invasive vulvar carcinoma among 20-to 44-year-old women between 2001 and 2018 in the United States [14].Therefore, some health policy actions like state mandates for HPV vaccination, increasing public awareness about HPV and vulvar cancer using education campaigns, and health insurance support to reduce the costs of HPV vaccination can be carried out in the United States [35].
This congruency of results between our study and those from high-income countries, such as Germany and the United Kingdom, could also be attributed to diagnostic advances and better access to healthcare.Improved diagnostic techniques and heightened awareness among healthcare providers can lead to earlier and more frequent detection of vulvar cancer cases.This, in turn, can result in an increase in reported incidence rates.In addition, improved access to healthcare services and cancer screening in high-income countries can result in better case detection and, subsequently, increased incidence rates.
Our study indicated that non-Hispanic White women had the highest incidence rate of vulvar cancer, with a relatively increasing trend among women of all racial or ethnic groups.Consistent with our results, Zhou et al. reported similar findings [7].Moreover, Watson et al. conducted a study acquiring data from two federal cancer surveillance programs, representing 92% of the United States population between 1999 and 2004, and declared similar results [36].Additionally, a study by Saraiya et al. analyzed data representing 83% of the United States population from 1998 to 2003 reported higher incidence rates of vulvar cancer in White women compared to women of other races or ethnicities [10].The reason for the highest incidence rate of vulvar cancer in non-Hispanic White women is still unclear.Possible explanations may be attributed to genetic susceptibility in the exposure to some underlying risk factors like HPV positivity, cigarette smoking, first sex before the age of 16 years, and more than one sex partner, which we cannot completely elucidate [37].Another potential reason could be that vulvar cancer is more common in older women [2], so variations in the age distribution of different racial or ethnic groups could influence the incidence rates.Additionally, genetic determinants could be a possible cause for the higher cancer incidence in White women [38].Evidence suggests that over 75% of vulvar cancer histotypes comprise SCCs [5,10]

| Strengths
The strengths of the current study consist of utilizing a highquality, reliable, nationwide, and population-based database to acquire and analyze data to assess the age-adjusted incidence rates, APCs, and AAPCs of different vulvar cancer histotypes among diverse racial or ethnic groups in the United States over 20 years from 2000 to 2019.Additionally, widely acknowledged and precise histologic definitions were used to classify various histologic types of vulvar cancer.

| Limitations
There were some limitations to the present study.First, we did not estimate the incidence rates, APCs, and AAPCs of vulvar cancer concerning geographical regions.Furthermore, the SEER databases, do not provide the necessary information to report other indicators such as disability-adjusted life years, years of life lost and years lived with disability.So, we could not report those indicators and this can be considered in the next iteration of the SEER database.Second, we could not evaluate the correlation between vulvar cancer incidence and the relevant risk factors, including HPV status or smoking, since this information is unavailable in the database.Third, there might be minor misclassification regarding patients' race or ethnicity because practitioners conducted the preliminary data collection.Fourth, adenocarcinoma only made up a few cases and rates of the total values.

| Conclusions
The incidence rates of vulvar cancer increased among women from all racial or ethnic groups, with a significantly increased trend in non-Hispanic Whites from 2000 to 2019.The findings may enable clinicians and healthcare officials to focus more on people from a particular race or ethnicity with a higher incidence rate of vulvar cancer to deliver more optimized and target-oriented care.We recommend that researchers report the epidemiology of vulvar cancer in the United States by relevant risk factors and update them regularly.

FIGURE 2 |
FIGURE 2 | Incident numbers and incidence rate of vulvar cancer in the United States in each age group.

TABLE 1 |
Demographic characteristics of vulvar cancer cases by the year of diagnosis.
a Median household income adjusted to 2021 inflation.b Unknown, missing, and no match.c Unknown, missing, no match, and Alaska or Hawaii.

TABLE 2 |
Rate of vulvar cancer in 2019 and from 2000 to 2019 in the United States and the average annual percent change in rates per 100 000, by race/ethnicity and cancer histology.
FIGURE 1 | Age-adjusted incidence rate of vulvar cancer over 2000-2019 and in 2020 in the United States, by race/ethnicity (A) and age (B).*p < 0.05.APC, annual percent change.

TABLE 3 |
Percent change in age-standardized incidence rates from 2019 to 2020, by race/ethnicity and age, using the November 2022 data submission.
[40]r study uncovered that SCC had the highest incidence rate among vulvar cancer histotypes.Notably, the incidence rate of SCC vulvar cancer was highest among non-Hispanic Whites, with a relatively increasing trend compared to other racial or ethnic groups.In 2018, Van Dyne et al. analyzed data between 1999 and 2015, covering approximately 97.8% of the United States population, and discovered a trend similar to our study among White women[39].In line with our results, a study by Akhtar-Danesh et al. using data from the Canadian Cancer Registry dataset between 1992 and 2008 and the American N SEER Program throughout 1973-2010 indicated that the incidence rate of invasive squamous cell vulvar cancer increased in both the United States and Canada[11].Furthermore, the results from a recent study by Berenson et al., including 88 942 patients with vulvar cancer using the USCS databases from 2001 to 2018, showed that the incidence of vulvar SCC was highest among non-Hispanic White women, which supports our findings[14].Prior research has indicated that vulvar SCC risk is linked to anogenital warts, smoking, alcohol use, and socioeconomic factors like marital status and education level[40].